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Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice

Oncogene volume 29, pages 2784–2794 (2010)Cite this article

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Abstract

The poor outcome of cancer gene therapy in clinical trials relates in part to insufficient gene delivery to tumor sites. Mesenchymal stem cells (MSCs) represent a new tool for the delivery of therapeutic agents to tumor cells. This study used an orthotopic nude mice model of hepatocellular carcinoma (HCC) to evaluate the potential of genetically modified human MSCs (hMSCs), to function as an effective delivery vehicle for therapeutic genes. hMSCs derived from the bone marrow were efficiently engineered to express human pigment epithelium-derived factor (PEDF) by lentiviral transduction, then tested in vitro for high-level expression and bioactivity of the transgenic protein. The preferential homing of hMSCs toward HCC was confirmed by in vitro and in vivo migration assays. in vivo efficacy experiments showed that intravenous (i.v.) injection of PEDF-expressing hMSCs significantly suppressed both the growth of primary liver tumors and the development of pulmonary metastases. Moreover, hMSCs-based PEDF gene delivery moderately increased the systemic levels of human PEDF. Immunohistochemistry of primary liver tumors demonstrated lower microvessel density in mice treated with hMSCs-PEDF than in control mice. This is the first study to show the potential of hMSCs as an effective delivery vehicle for therapeutic genes in the treatment of HCC.

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Abbreviations

CM:

conditioned media

ELISA:

enzyme-linked immunosorbent assay

GFP:

green fluorescence protein

HCC:

hepatocellular carcinoma

hMSC:

human mesenchymal stem cell

IRES:

internal ribosomal entry site

i.v.:

intravenous

MSC:

mesenchymal stem cell

PBS:

phosphate-buffered saline

PEDF:

pigment epithelium-derived factor

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Acknowledgements

This study was supported by grants from Jiangsu Province's Outstanding Medical Academic Leader program (RC2007057 to BS and YG), Jiangsu Province's Key Medical Centre (2006-50 to XW) and grants from the Natural Science Foundation of China (30672367 and 30772003 to BS), Ministry of Health, China (Wkj2006-2-021 to BS), New Century Excellent Talents in University, the Ministry of Education (To BS).

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Authors and Affiliations

  1. Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, PR China

    Y Gao, A Yao, W Zhang, S Lu, Y Yu, L Deng, A Yin, Y Xia, B Sun & X Wang

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  1. Y Gao
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Correspondence to B Sun or X Wang.

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Gao, Y., Yao, A., Zhang, W. et al. Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice. Oncogene 29, 2784–2794 (2010). https://doi.org/10.1038/onc.2010.38

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